tbuckley/cabot-search huggingface dataset:
Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma
Authors: Ajai Chari, Monique C. Minnema, Jesus G. Berdeja, Albert Oriol, Niels W.C.J. van de Donk, Paula Rodríguez-Otero, Elham Askari, María-Victoria Mateos, Luciano J. Costa, Jo Caers, Raluca Verona, Suzette Girgis, Shiyi Yang, Rachel B. Goldsmith, Xiang Yao, Kodandaram Pillarisetti, Brandi W. Hilder, Jeffery Russell, Jenna D. Goldberg, Amrita Krishnan
Journal: New England Journal of Medicine (2022)

G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells.In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 μg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 μg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study.At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 μg per kilogram weekly [30 patients] and 800 μg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-μg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-μg dose level) and 4.2 months (in those who had received it at the 800-μg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively.Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.).
pH and Thrombin Concentration Are Decisive in Synthesizing Stiff, Stable, and Open‐Porous Fibrin‐Collagen Hydrogel Blends without Chemical Cross‐Linker
Authors: Mattis Wachendörfer, Eva Miriam Buhl, Ghazi Ben Messaoud, Walter Richtering, Horst Fischer
Journal: Advanced Healthcare Materials (2022)

Fibrin-collagen hydrogel blends exhibit high potential for tissue engineering applications. However, it is still unclear whether the underlying cross-linking mechanisms are of chemical or physical nature. It is here hypothesized that chemical cross-linkers play a negligible role and that instead pH and thrombin concentration are decisive for synthetizing blends with high stiffness and hydrolytic stability. Different fibrin-collagen formulations (pure and with additional transglutaminase) are used and the blends' compaction rate, hydrolytic stability, compressive strength, and hydrogel microstructure are investigated. The effect of thrombin concentration on gel compaction is examined and the importance of pH control during synthesis observed. It is revealed that transglutaminase impairs gel stability and it is deduced that fibrin-collagen blends mainly cross-link by mechanical interactions due to physical fibril entanglement as opposed to covalent bonds from chemical cross-linking. High thrombin concentrations and basic pH during synthesis reduce gel compaction and enhance stiffness and long-term stability. Scanning electron microscopy reveals a highly interpenetrating fibrous network with unique, interconnected open-porous microstructures. Endothelial cells proliferate on the blends and form a confluent monolayer. This study reveals the underlying cross-linking mechanisms and presents enhanced fibrin-collagen blends with high stiffness, hydrolytic stability, and large, interconnected pores; findings that offer high potential for advanced tissue engineering applications.
Oh NO! Loss of PHD2 leads to “radical” changes in the lung vasculature
Authors: Mark L. Ormiston, Robert P. Jankov, Duncan J. Stewart
Journal: European Respiratory Journal (2022)

<b>The PHD2 deficient mouse model of nitrative stress provides an excellent opportunity to explore these important relationships, potentially providing critical insight into the pathogenesis of PAH</b> https://bit.ly/3r66aBF
Pleuroparenchymal fibroelastosis: so many unmet needs
Authors: Philippe Bonniaud, Vincent Cottin, Guillaume Beltramo
Journal: European Respiratory Journal (2022)

<b>With numerous unanswered questions and clinical challenges, significant challenges remain for the management of pleuroparenchymal fibroelastosis. Registries and prospective trials should be encouraged for the future.</b> https://bit.ly/3Tlq6gb
Diagnostic Aspects of X-ray Examination of the Cervical Spine of Children with Complaints on Headache
Authors: I. O. Erenkov, R. O. Zorina, V. A. Voronin
Journal: Radiology - Practice (2022)

Purpouse – to define of diagnostic significance of x-ray examination of the cervical spine of children with complaints on headache. Retrospective comparative study was conducted. During the research, 159 medical histories of children from 5 to 17 years were analyzed: patients had complaints on headache and standard and functional x-ray examination of the cervical spine was prescribed and performed. 59 of those patients also had sonography examination of the vertebral arteries, and in 38 medical histories contained results of functional sonography test (examination of vertebral arteries in the middle and rotation positions of the head). All medical histories of children were divided in 3 groups based on the curvature of the cervical spine (p ≤ 0,01). Assessment of values of mobility indicators in the cervical spine, based on Kolmogorov-Smirnov criteria, revealed normal distributions in all three groups. Comparative analysis of values of the segmental mobility in the cervical spine in all 3 groups didn’t reveal statistically significant differences (p &gt; 0,05). The significant correlation between values of sonography examination of the vertebral arteries, values of functional sonography tests and values of the segmental mobility in the cervical spine was not revealed. The x-ray examination of the cervical spine is not prioritized method of diagnostics in children with headache. Found cases of increasing segmental mobility in the cervical spine had not demonstrated significant change in blood flow in vertebral arteries in children. Prescription of X-ray of the cervical spine must be strictly justified recommendation if patients are children with complaints on headaches.
Glomerular diseases in pregnancy: pragmatic recommendations for clinical management
Authors: Fadi Fakhouri, Nora Schwotzer, Gianfranca Cabiddu, Jonathan Barratt, Hélène Legardeur, Vesna Garovic, Alejandra Orozco-Guillen, Jack Wetzels, Eric Daugas, Gabriella Moroni, Marina Noris, Vincent Audard, Manuel Praga, Elisa Llurba, Grégoire Wuerzner, Rossella Attini, David Desseauve, Elena Zakharova, Claudio Luders, Kate Wiles, Filomena Leone, Shilpanjali Jesudason, Nathalie Costedoat-Chalumeau, Andrea Kattah, Virgilia Soto-Abraham, Alexandre Karras, Jai Prakash, Liz Lightstone, Pierre Ronco, Claudio Ponticelli, Gerald Appel, Giuseppe Remuzzi, Vassilis Tsatsaris, Giorgina Barbara Piccoli
Journal: Kidney International (2022)
Abstract 3145: Mortal Interaction of Sleep Apnea with Ischemic, But Not Non-Ischemic Heart Failure
Authors: Dai Yumino, Hanqiao Wang, Gary E Newton, Susanna Mak, John D Paker, John S Floras, T D Bradley
Journal: Circulation (2007)

Introduction: Past studies showed that in patients with heart failure (HF), sleep apnea (SA) increases mortality risk, but these patients were not characterized on the basis of HF etiology. Hypothesis: Since patients with ischemic HF may suffer greater adverse consequences of SA-related hypoxia and hypertension than those with non-ischemic HF, SA will increase risk of death in patients with ischemic, but not in those with non-ischemic HF. Methods: From 1997 to 2004, consecutive HF patients with ejection fraction (EF) ≤ 45% had sleep studies and were divided into those with SA (apnea-hypopnea index ≥ 15/hr of sleep) and those without SA. They were followed prospectively to determine all-cause mortality rate. Results: Of 218 patients enrolled, follow up data were obtained in 95%. Of these, 87 (40%) had ischemic HF. SA was found in 53% of those with ischemic HF and in 41% of those with non-ischemic HF. 14 patients with obstructive sleep apnea on CPAP therapy were excluded from the analysis. Of the remaining 193 patients, 34 (18%) died during a mean follow up of 32 months. In the non-ischemic HF group, there was no difference in mortality between those with, and those without SA (Figure ). In contrast, in the ischemic group, mortality was significantly higher in those with SA than those without it (18.9 vs. 4.6 deaths/100 patient-years, P = 0.003). After adjusting for age, EF, New York Heart Association class, β-blocker use, and the presence of diabetes using multivariate Cox analysis, SA remained a significant independent risk for death (HR 3.02, 95%CI 1.07– 8.59, P = 0.037). Conclusions: These data show that ischemic etiology identifies those HF patients with SA at increased risk of death.
Cytokines as prognostic biomarkers in pulmonary arterial hypertension
Authors: Athénaïs Boucly, Ly Tu, Christophe Guignabert, Christopher Rhodes, Pascal De Groote, Grégoire Prévot, Emmanuel Bergot, Arnaud Bourdin, Antoine Beurnier, Anne Roche, Mitja Jevnikar, Xavier Jaïs, David Montani, Martin R. Wilkins, Marc Humbert, Olivier Sitbon, Laurent Savale
Journal: European Respiratory Journal (2022)

Background Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH. Methods This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients. Results Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort. Conclusion The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.
RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD
Authors: Hannelore P. Van Eeckhoutte, Chantal Donovan, Richard Y. Kim, Thomas M. Conlon, Meshal Ansari, Haroon Khan, Ranjith Jayaraman, Nicole G. Hansbro, Yves Dondelinger, Tom Delanghe, Allison M. Beal, Brad Geddes, John Bertin, Tom Vanden Berghe, Joyceline De Volder, Tania Maes, Peter Vandenabeele, Bart M. Vanaudenaerde, Dieter Deforce, Sonja Škevin, Filip Van Nieuwerburgh, Fien M. Verhamme, Guy F. Joos, Sobia Idrees, Herbert B. Schiller, Ali Önder Yildirim, Alen Faiz, Mathieu J.M. Bertrand, Guy G. Brusselle, Philip M. Hansbro, Ken R. Bracke
Journal: European Respiratory Journal (2022)

Background Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD. Methods We assessed RIPK1 expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1 S25D/S25D kinase-deficient mice and the RIPK1 kinase inhibitor GSK′547. Results RIPK1 expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increased Ripk1 expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition. Conclusions RIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.
Reply to: Risk factors for disease progression in fibrotic hypersensitivity pneumonitis
Authors: M. Malik Farooqi, Nathan Hambly, Christopher J. Ryerson, Martin Kolb
Journal: European Respiratory Journal (2022)

<b>In a Canadian population with fibrotic hypersensitivity pneumonitis, only the presence of an identified antigen is associated with lower risk of progressive fibrosing interstitial lung disease</b>https://bit.ly/3FAcSqB
Improving pulmonary function test interpretation
Authors: Thomas P. Presti, Douglas C. Johnson
Journal: European Respiratory Journal (2022)

<b>Improvements are needed to the 2022 ERS/ATS lung function test interpretative strategies with regard to BDR criteria, % predicted, and the algorithm for <i>D</i><sub>LCO</sub> interpretation, which should include % predicted <i>D</i><sub>LCO</sub> adjusted for lung volume</b>https://bit.ly/3CvYori
A reply to questions raised about FEV<sub>1</sub>Q and bronchodilator responsiveness
Authors: Martin R. Miller, Sanja Stanojevic, David A. Kaminsky, Bruce R. Thompson
Journal: European Respiratory Journal (2022)

We thank K. Rurak and H. Schotland for their feedback on the recent statements on assessing lung function changes over time in the European Respiratory Society (ERS)/American Thoracic Society (ATS) technical standard on pulmonary function test (PFT) interpretive strategies [1]. We accept that the section related to natural changes in lung function over time was limited and this was not ideal. For changes over time we could only comment on forced expiratory volume in 1 s (FEV1) as there is a lack of data for the other indices. This is a major gap in the literature that needs to be addressed. The recent ATS/ERS technical standard on pulmonary function test interpretive strategies is based on the available evidence <https://bit.ly/3hgQsm1>
Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease
Authors: Sven Schneider, Katharina Poglitsch, Christina Morgenstern, Tamara Quint, Katharina Gangl, Christoph Sinz, Tina Bartosik, Nicholas James Campion, David Tianxiang Liu, Lukas David Landegger, Aldine Tu, Victoria Stanek, Marianne Rocha-Hasler, Christine Bangert, Julia Eckl-Dorna
Journal: European Respiratory Journal (2022)

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) comprises the triad of chronic rhinosinusitis with nasal polyps, asthma and intolerance to NSAIDs. Dupilumab treatment, targeting the interleukin-4 (IL-4) receptor α, significantly reduces polyp burden as well as asthma symptoms. Here we aimed to investigate the effect of dupilumab on aspirin intolerance, burden of disease and nasal cytokine profiles in patients with N-ERD.In this open-label trial, adult patients with confirmed N-ERD were treated with dupilumab for 6 months. Clinical parameters (e.g. total polyp scores, quality of life questionnaires, smell test, spirometry), oral aspirin provocation testing and blood, nasal and urine sampling were monitored at regular intervals for up to 6 months after starting dupilumab therapy.Of the 31 patients included in the study, 30 completed both aspirin provocation tests. After 6 months of treatment with dupilumab, 23% of patients (n=7 of 30) developed complete aspirin tolerance and an additional 33% of patients (n=10 of 30) tolerated higher doses. Polyp burden was significantly reduced (total polyp score: -2.68±1.84, p<0.001), while pulmonary symptoms (asthma control test: +2.34±3.67, p<0.001) and olfactory performance improved (University of Pennsylvania Smell Identification Test: +11.16±9.54, p<0.001) in all patients after therapy. Patients with increased aspirin tolerance showed a significant decrease in urinary leukotriene E4 levels and their improvement in clinical parameters was associated with a reduction of eotaxin-1, C-C motif chemokine ligand 17, IL-5, IL-17A and IL-6.In this study, 57% of N-ERD patients tolerated higher doses of aspirin under dupilumab therapy.
Two‐Dimensional Mg<sub>2</sub>Si Nanosheet‐Enabled Sustained Hydrogen Generation for Improved Repair and Regeneration of Deeply Burned Skin
Authors: Yanxia Zhu, Qi Jiang, Zhaokui Jin, Danyang Chen, Qingqing Xu, Jinchun Chen, Yue Zeng, Shengqiang Chen, Qianjun He
Journal: Advanced Healthcare Materials (2022)

Molecular hydrogen holds a high potential for wound healing owing to its anti-inflammatory effect and high biosafety, but commonly used hydrogen administration routes hardly achieve the sustained supply of high-dosage hydrogen, limiting hydrogen therapy efficacy. Here, two-dimensional Mg2 Si nanosheet (MSN) is exploited as a super-persistent hydrogen-releasing nanomaterial with high biocompatibility, and the incorporation of MSN into the chitosan/hyaluronic acid hydrogel (MSN@CS/HA) is developed as a dressing to repair deeply burned skin. The MSN@CS/HA hydrogel dressing can continuously generate hydrogen molecules for about 1 week in the physiological conditions in support of local, long-term, and plentiful hydrogen supply and remarkably promotes the healing and regeneration of deep second-degree and third-degree burn wounds without visible scar and toxic side effect. Mechanistically, a sustained supply of hydrogen molecules induces anti-inflammatory M2 macrophage polarization in time by enhancing CCL2 (chemokine C-C motif ligand 2) expression to promote angiogenesis and reduce fibrosis and also enhances the proliferation and migration capability of skin cells directly and indirectly by locally scavenging overexpressed reactive oxygen species, synergistically favoring wound repair. The proposed synthesis method, therapeutic strategy, and mechanisms will open a window for synthesizing a variety of MSene nanomaterials and developing their various proangiogenesis applications besides wound healing.
Thyroid‐on‐a‐Chip: An Organoid Platform for In Vitro Assessment of Endocrine Disruption
Authors: Daniel J. Carvalho, Anna M. Kip, Mírian Romitti, Marta Nazzari, Andreas Tegel, Matthias Stich, Christian Krause, Florian Caiment, Sabine Costagliola, Lorenzo Moroni, Stefan Giselbrecht
Journal: Advanced Healthcare Materials (2022)

Thyroid is a glandular tissue in the human body in which the function can be severely affected by endocrine disrupting chemicals (EDCs). Current in vitro assays to test endocrine disruption by chemical compounds are largely based on 2D thyroid cell cultures, which often fail to precisely evaluate the safety of these compounds. New and more advanced 3D cell culture systems are urgently needed to better recapitulate the thyroid follicular architecture and functions and help to improve the predictive power of such assays. Herein, the development of a thyroid organoid-on-a-chip (OoC) device using polymeric membranous carriers is described. Mouse embryonic stem cell derived thyroid follicles are incorporated in a microfluidic chip for a 4 day experiment at a flow rate of 12 µL min-1 . A reversible seal provides a leak-tight sealing while enabling quick and easy loading/unloading of thyroid follicles. The OoC model shows a high degree of functionality, where organoids retain expression of key thyroid genes and a typical follicular structure. Finally, transcriptional changes following benzo[k]fluoranthene exposure in the OoC device demonstrate activation of the xenobiotic aryl hydrocarbon receptor pathway. Altogether, this OoC system is a physiologically relevant thyroid model, which will represent a valuable tool to test potential EDCs.